Use of platelet rich plasma composition in the treatment of cardiac conduction abnormalities

ABSTRACT

Methods and kits for treating a cardiac arrhythmia using a platelet rich plasma (PRP) composition are provided. Any type of arrhythmia may be treated using the PRP composition. The PRP composition may comprise PRP developed using blood collected from a patient suffering the cardiac arrhythmia. The PRP composition may be buffered to a physiological pH and may include one or more anti-arrhythmic agents, anti-coagulants, or other drugs. The PRP composition may be delivered using a nebulizer, minimally invasively, or surgically. In some embodiments, the PRP composition may be coated on one or more medical devices. The PRP composition may be delivered to an identified portion of the electrical conduction system of the heart affected and/or causing the arrhythmia to occur.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to treatment of cardiac conditions andmore specifically to treatment of a cardiac conduction abnormality(e.g., arrhythmia) using a composition comprising platelet rich plasma.

2. Description of the Related Art

Arrhythmias are a common disorder where the regular electric pacemakeractivity of the heart may be disturbed. The disturbance may be caused bya blockage, delay, or misfiring of the electrical conduction system ofthe heart that controls the contraction and relaxation of the cardiacmuscle. Arrhythmias may vary in severity, from asymptomatic disease tosudden cardiac death, and may lead to heart disease and stroke.According to the American Heart Association, about 2.2 million Americanssuffer from atrial fibrillation, one type of arrhythmia.

To maintain regular, rhythmic beating, the heart comprises an electricalconduction system that controls the contraction of the cardiac muscle.FIG. 1 is a depiction of the electrical conduction system of a heart(100). In a normal rhythm, an impulse begins in the sino-atrial (SA)node (102) and is ultimately propagated to the myocardium to maintainblood flow through the heart. The SA node (102) is located adjacent tothe right atrium (RA) and initiates an impulse. The impulse is thenpropagated to the left atrium (LA) via the intra-atrial pathway (104)and via the internodal pathways (106) to the atrioventricular (AV) node(108). This first propagation causes the atria to contract so that theblood flows from the atria into the ventricles. After a delay at the AVnode (108), the impulse propagates to the left ventricle (LV) and theright ventricle (RV) through the Bundle of His (110) to the left bundlebranches (112) and the right bundle branches (114). The ventriclescontract when the impulse reaches the Purkinje fibers (116). In amedical setting, this sequence may be measured in an electrocardiogram(ECG or EKG) that records the electrical activity of the heart over timeand may be recognized as a PQRST-wave.

Any disturbance in the electrical conduction of the heart may betypically considered to be an arrhythmia. Arrhythmias may be acute,chronic, and/or a combination of various arrhythmias. Disturbances inelectrical conduction may classified by rate, mechanism, and/or site oforigin. The mechanisms that may cause an arrhythmia include, forexample, pre-excitation (e.g. from a bypass tract), automaticity,reentry, and triggered activity. The site of origin of the arrhythmiamay be anywhere in the electrical conduction system and may be, forexample, atrial, junctional, atrio-ventricular, and/or ventricular.

Arrhythmias may result in irregular rhythms, reduced heart rates(bradycardia), accelerated heart rates (tachycardia), or desynchronizedheart muscle contractions which may reduce the mechanical function ofthe heart. For example, atrio-ventricular dyssynchrony, may cause theloss of the “atrial kick” which facilitates ventricular filling, orresult in an atrium contracting against a closed atrio-ventricularvalve. Ventricular dyssynchrony, where the left and right ventriclescontract at different times, may reduce contractile efficiency when oneventricle is contracting while the other ventricle is relaxed, and mayresult in interventricular septal displacement that reduces the netforward blood flow of the ventricle. In still another example, atrialfibrillation results in a disorganized quivering of the atrial muscleand a loss of forward flow, which may predispose the patient to bloodclot formation and a higher risk of stroke.

Arrhythmias may be treated in several ways, including, for example,physical maneuvers, anti-arrhythmic agents, other drugs, electricalpacing, radiofrequency ablation, and/or cryo-cautery. The treatment istypically selected based on a diagnosis that identifies the rate, site,and/or mechanism of the arrhythmia(s) to be treated. While sometreatments may relieve some arrhythmias, the same treatments mayaggravate or have no effect on other arrhythmias. For example, aphysical maneuver such as a Valsalva maneuver or carotid sinus massagemay be used to treat a superventricular tachycardia, but may not affecta ventricular tachycardia or a bradycardia.

Drug treatments that may be used to treat arrhythmias may haveundesirable side effects and/or may be required for months if not yearsin order to maintain a regular heart rate. Indeed, some anti-arrhythmicagents even predispose a patient to an increased risk of certainarrhythmias. Hemodynamically unstable patients suffering an acutearrhythmia may be treated with electrical shocks using an automaticexternal defibrillator (AED) or manual defibrillator, but electricalshocks are not always successful in ending an arrhythmia and may causesignificant discomfort or even burn the skin. Patients with a chronicarrhythmia may be treated with implantable cardiac rhythm managementdevices such as a pacemaker and/or defibrillator. However, these devicesare subject to malfunction and may be difficult to implant in certainpatients. Ablation of abnormal conduction pathways, or the formation ofscar tissue to control the propagation of electrical activity, such asthe Maze procedure used for atrial fibrillation, also requires invasiveprocedures and may only be effective in treating a narrow range ofarrhythmias and while also increasing the patient's arrhythmia riskduring the procedure or surgery.

As such, additional treatments for arrhythmias are desirable. Kits fortreating arrhythmias are also desirable.

SUMMARY

Methods for treating cardiac conduction abnormalities (e.g.,arrhythmias) are provided. Generally, the methods may includeidentifying a patient with a cardiac arrhythmia or an arrhythmia riskand delivering a platelet rich plasma (PRP) composition comprising PRPto treat the cardiac conduction abnormality. The cardiac conductionabnormality may be determined based on an abnormal heart beat, anelectrocardiogram (ECG), electrophysiology study or by any othersuitable mechanism. The functional effect of the conduction abnormalitymay also be assessed using electrocardiography, echocardiography,cardiac catheterization, cardiac magnetic resonance imaging, or cardiacnuclear medicine imaging. The cardiac abnormality or a heightened riskof a cardiac abnormality may be documented in, for example, a medicalhistory, test results, patient file, procedure log, or other electronicor paper record. The PRP composition may be delivered to cardiac tissuein an amount sufficient to treat the conduction abnormality. Forexample, the amount may be about one to about three cubic centimeters,about three to about five cubic centimeters, about five to about sevencubic centimeters, or seven or more cubic centimeters. The PRPcomposition may comprise a platelet rich plasma, a buffering agent,and/or an anti-arrhythmic agent. In some examples, the PRP compositionmay be injected into the heart muscle or infused into one or moreregions of the cardiac vasculature. The injection or infusion may beperformed in a translumenal access procedure, a thorascopic procedure,an open chest procedure or any other access procedure.

The cardiac conduction abnormality may be associated with any of avariety of cardiac arrhythmias or arrhythmia risks. In some variations,the arrhythmia may be a bradycardia or a tachycardia, such as aventricular tachycardia, for example. The arrhythmia may be caused atleast in part by triggered activity, pre-excitation, automaticity,reentry, or by another mechanism, or a combination of mechanisms. Thearrhythmia may be chronic, acute, or episodic. The arrhythmia may bediagnosed using an electrocardiogram generated by an electrocardiograph,a Holter monitor, or a cardiac event monitor.

In some variations, the PRP composition may be prepared from whole bloodof the patient. The whole blood may be drawn prior to the arrhythmia orduring the conduction abnormality. The PRP composition may be bufferedto any suitable pH. In some examples, the suitable pH may be aphysiological pH between about 7.3 and about 7.5.

The PRP composition may be delivered using any suitable medicalprocedure. For example, the PRP may be delivered using a minimallyinvasive procedure or an open or limited access surgical procedure. Forexample, a PRP composition may be delivered to, or adjacent to, asino-atrial (SA) node, an atrio-ventricular (AV) node, Purkinje fibers,or another suitable region of the heart using a catheter configured toinject the PRP composition directly into the tissue, or configured toselectively infuse branches of the cardiac vasculature perfusing thetissue corresponding to the conduction system target site (or ischemicarea of the myocardium). Systemic treatment with PRP is alsocontemplated, including peripheral infusion as well as an inhalable PRPcomposition.

The PRP composition may be used to treat a patient who may be presentlyexhibiting an arrhythmia, or a patient with an intermittent arrhythmiaor at-risk of an arrhythmia but without overt rate or conductiondisturbance at the time of PRP treatment. For example, a patient withWolff-Parkinson-White syndrome may be treated using the PRP compositioneven if the heart is not tachycardic at the time of treatment. Further,the PRP composition may be administered at any suitable time during orfollowing an acute arrhythmia. To illustrate, the PRP composition may bedelivered within about one minute, about five minutes, about fifteenminutes, about thirty minutes, about one hour, several hours, days, orweeks following the acute arrhythmia.

The PRP composition may comprise PRP alone or PRP with one or moreadditional agents, and may be prepared in any suitable way. For example,the PRP composition may be prepared by adding an anti-arrhythmic agentto PRP. The anti-arrhythmic agent may be, but is not limited to, asodium channel blocker, a beta blocker, a potassium channel blocker, acalcium channel blocker, or any other suitable anti-arrhythmic agent.The PRP composition may also comprise other suitable active agents suchas anti-coagulants or clotting agents.

The methods may further comprise monitoring the cardiac conductionabnormality before, during, and/or after delivering the PRP composition.The monitoring may be initiated after the delivery by, for example,attaching a Holter monitor (or event monitor) to the patient.

Kits for treating the arrhythmia are also provided. The kits may includeany suitable components. For example, a kit may comprise one or morepreparation devices for preparing the PRP (e.g., a centrifuge) and oneor more delivery devices configured to deliver a PRP composition toconduction tissue of a heart. The kit may also comprise one or moreanti-arrhythmic agents.

The kits may further comprise one or more collection devices forcollecting blood from a patient. The blood may be collected from apatient that has suffered or may be suffering from a cardiac conductionabnormality. In some embodiments, the blood may be collected from apatient who is suffering a myocardial infarction that may, in turn,increase the patient's risk of arrhythmia. The kit may additionallycomprise instructions for using one or more of the kit components.

Embodiments of the invention are directed to methods of reducingconduction resistance to an electrical stimulation device designed tomaintain cardiac rhythm by delivering a composition containing plateletrich plasma to an area of cardiac tissue, in which the electricalstimulation device is operably coupled to cardiac tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic depiction of the electrical conduction system of aheart.

FIG. 2 is a schematic illustration of the cardiac vasculature.

FIG. 3 shows Left Ventricle ejection fraction by MRI 3 weeks after heartattack in mouse ischemia-reperfusion model.

FIGS. 4 a-4 d show an electrocardiogram and ventricular pressure levelsof a test subject before and after treatment of a reperfusion arrhythmiawith PRP.

DETAILED DESCRIPTION Overview

The term “arrhythmia” is used broadly herein to refer to cardiacabnormalities involving a disturbance in initialization and/orpropagation of the impulses in a heart. As discussed above, thedisturbance may be localized to a portion of the conduction tissuesand/or may affect the entire electrical conduction system of the heart.There are several possible types of arrhythmias of varying severity.

As mentioned previously, an arrhythmia may be initially detected in apatient as an abnormally fast (i.e., tachycardia) or slow (i.e.,bradycardia) heartbeat. Furthermore, some arrhythmias or conductionpatterns may be characterized as regular, irregularly irregular (e.g.,atrial fibrillation) or regularly irregular (e.g., Wenckebach or seconddegree heart block—type 1). The specific type of arrhythmia from which apatient may be suffering may be diagnosed based on an electrocardiogram(ECG or EKG). A normal electrocardiogram, as is known, depicts aPQRST-wave. The specific arrhythmia may be diagnosed based on one ormore deviations from a normal PQRST-wave.

The term “PRP” as used herein is a broad term which is used in itsordinary sense and is a concentration of platelets greater than theperipheral blood concentration suspended in a solution of plasma. Whilenormal platelet counts may range from about 140,000 to about 400,000 permicroliter, some platelet concentrations of PRP may be in the range ofabout 500,000 to about 1,200,000 per cubic millimeter or more, and someplatelet concentrations may be as low as 50,000 per cubic millimeter.PRP may be formed from whole blood, and may be obtained usingautologous, allogenic, or pooled sources of platelets and/or plasma. PRPmay be formed from a variety of animal sources, including human sources.In some examples, PRP may be further processed, including but notlimited to leukoreduction and immunoadsorbtion. Other PRP compositionsare further described in U.S. Pat. No. 6,811,777 to Mishra filed Apr.11, 2003, which is hereby incorporated herein by reference in itsentirety.

Various methods for delivering a PRP composition into conduction tissuesof the heart to treat an arrhythmia are disclosed. In variousembodiments, the composition may be delivered to the conduction tissues,the region of tissue directly adjacent to the conduction tissue, and/orhealthy tissue. The PRP composition may comprise a platelet gel, orflowable material or liquid, other substances described herein, or anysubstance suitable for providing the desired level of treatment of theconduction tissues.

The PRP composition may be delivered to a patient in an emergencysituation or as part of an elective procedure. For example, the PRPcomposition may be delivered in an emergency room to treat a ventriculartachycardia. In other instances, the PRP composition may be deliveredweeks after an arrhythmia during an elective cardioversion.

In the treatment of cardiac conditions, the area known as “Koch'sTriangle” (where a significant portion of the conduction tissues,including the AV node, is located) is typically avoided or treated withspecial care during cardiac surgery. Koch's Triangle is a portion of theright atrium defined generally by the coronary sinus, Todaro's tendon,the limbus ovalis, and the annulus of the tricuspid valve.

The PRP composition may be useful in treating arrhythmias that cause, orare caused by, a myocardial infarction. The myocardial infarction may beidentified by determining whether enzymes such as cardiac troponin(e.g., troponin-I or T), creatine kinase (CK) including CK-MB, aspartatetransminase (AST)/Glutamic Oxaloacetic Transaminase (GOT/SGOT)/aspartateaminotransferase (ASAT), lactate dehydrogenase (LDH), and/or myoglobin(Mb), and/or the like are present in the blood stream. The PRPcompositions described herein may be delivered in the absence of theenzymes. Myocardial infarctions may be determined by identifying STelevation in an ECG (e.g., during rest, a pharmacological stress test,and/or a physiological stress test), by coronary angiogram (e.g., notingacute closure of a vessel supplying myocardium at risk), by a nuclearmedicine scan (e.g., technetium-99m or thalium-201), etc.

Further, according to some embodiments, the PRP composition may comprise

PRP and one or more active agents. For example, the active agents mayinclude anti-arrhythmic agents and/or anti-coagulants.

The compositions, devices, methods, and kits described herein areillustrative of various embodiments, variations, and adaptations. Thedisclosure is not intended to be limited to only the embodimentsdescribed.

Compositions

The PRP composition may comprise a PRP derived from a human or animalsource of whole blood. The PRP may be prepared from an autologoussource, an allogenic source, a single source, or a pooled source ofplatelets and/or plasma. To derive the PRP, whole blood may becollected, for example, using a blood collection syringe. The amount ofblood collected may depend on a number of factors, including, forexample, the amount of PRP desired, the health of the patient, theseverity or type of the arrhythmia, the availability of prepared PRP, orany suitable combination of factors. Any suitable amount of blood may becollected. For example, about 20 cc to about 150 cc of blood may bedrawn. More specifically, about 27 cc to about 110 cc or about 27 cc toabout 55 cc of blood may be withdrawn. In some embodiments, the bloodmay be collected from a patient who may be presently suffering, or whohas previously suffered from, a cardiac arrhythmia. PRP made from apatient's own blood may significantly reduce the risk of adversereactions or infection.

The PRP may be prepared in any suitable way. For example, the PRP may beprepared from whole blood using a centrifuge. The whole blood may or maynot be cooled after being collected. Isolation of platelets from wholeblood depends upon the density difference between platelets and redblood cells. The platelets and white blood cells are concentrated in thelayer (i.e., the “buffy coat”) between the platelet depleted plasma (toplayer) and red blood cells (bottom layer). For example, a bottom buoyand a top buoy may be used to trap the platelet-rich layer between theupper and lower phase. This platelet-rich layer may then be withdrawnusing a syringe or pipette. Generally, at least 60% or at least 80% ofthe available platelets within the blood sample can be captured. Theseplatelets may be resuspended in a volume that may be about 3% to about20% or about 5% to about 10% of the sample volume.

In an exemplary embodiment, about 55 cc of blood may be withdrawn into a60 cc syringe (or another suitable syringe) that contains about 5 cc ofan anticoagulant, such as a citrate dextrose solution. The syringe maybe attached to an apheresis needle, and primed with the anticoagulant.Blood (about 27 cc to about 55 cc) may be drawn from the patient usingstandard aseptic practice. In some embodiments, a local anesthetic suchas anbesol, benzocaine, lidocaine, procaine, bupivicaine, or anyappropriate anesthetic known in the art may be used to anesthetize theinsertion area.

In some examples, the blood may then be centrifuged using agravitational platelet system, such as the Cell Factor Technologies GPSSystem® centrifuge. The blood-filled syringe containing between about 20cc to about 150 cc of blood (e.g., about 55 cc of blood) and about 5 cccitrate dextrose may be slowly transferred to a disposable separationtube which may be loaded into a port on the GPS centrifuge. The samplemay be capped and placed into the centrifuge. The centrifuge may becounterbalanced with about 60 cc sterile saline, placed into theopposite side of the centrifuge. Alternatively, if two samples areprepared, two GPS disposable tubes may be filled with equal amounts ofblood and citrate dextrose. The samples may then be spun to separateplatelets from blood and plasma. The samples may be spun at about 2000rpm to about 5000 rpm for about 5 minutes to about 30 minutes. Forexample, centrifugation may be performed at 3200 rpm for extraction froma side of the separation tube and then isolated platelets may besuspended in about 3 cc to about 5 cc of plasma by agitation. The PRPmay then be extracted from a side port using, for example, a 10 ccsyringe. If about 55 cc of blood may be collected from a patient, about5 cc of PRP may be obtained.

The PRP composition may be delivered to help facilitate properconduction. For example, the PRP composition may excite, slow orstabilize conduction pathways or various foci in the heart, orfacilitate development of conduction pathways. For example, in the caseof a blocked AV node, the PRP composition may provide an auxiliaryconduction pathway and/or allow the existing (blocked) pathway to heal.In contrast, if the conduction tissue is spontaneously firing, the PRPcomposition may facilitate non-conductive tissue growth that does notpropagate errant impulses.

As the PRP composition comprises activated platelets, active agentswithin the platelets are released. These agents include, but are notlimited to, cytokines (e.g., IL-1B, IL-6, TNF-A), chemokines (e.g.,ENA-78 (CXCL5), IL-8 (CXCL8), MCP-3 (CCL7), MIP-1A (CCL3), NAP-2(CXCL7), PF4 (CXCL4), RANTES (CCL5)), inflammatory mediators (e.g.,PGE2), and growth factors (e.g., Angiopoitin-1, bFGF, EGF, FGF, HGF,IGF-I, IGF-II, PDAF, PDEGF, PDGF AA and BB, TGF-.beta. 1, 2, and 3, andVEGF).

The PRP composition may be delivered as a liquid, a solid, a semi-solid(ex., a gel,), an inhalable powder, or some combination thereof. Whenthe PRP is delivered as a liquid, it may comprise a solution, anemulsion, a suspension, etc. A PRP semi-solid or gel may be prepared byadding a clotting agent (e.g., thrombin) to the PRP. The gel may be moreviscous than a solution and therefore may better preserve its positiononce it is delivered to target tissue. Further, the PRP may be dried toform an inhalable powder.

In some instances, it may be desirable to deliver the PRP composition asa liquid and have it gel or harden in situ. For example, the PRPcompositions may include, for example, collagen, cyanoacrylate,adhesives that cure upon injection into tissue, liquids that solidify orgel after injection into tissue, suture material, agar, gelatin,light-activated dental composite, other dental composites, silk-elastinpolymers, Matrigel® gelatinous protein mixture (BD Biosciences),hydrogels and/or other suitable biopolymers. Alternatively, the abovementioned agents need not form part of the PRP mixture. For example, theabove mentioned agents may be delivered to the target tissue after thePRP has been delivered to the target tissue to cause the PRP to gel. Insome embodiments, the PRP composition may harden or gel in response toone or more environmental or chemical factors such as temperature, pH,proteins, etc.

The PRP may be buffered using an alkaline buffering agent to aphysiological pH. The buffering agent may be a biocompatible buffer suchas HEPES, TRIS, monobasic phosphate, monobasic bicarbonate, or anysuitable combination thereof that may be capable of adjusting the PRP tophysiological pH between about 6.5 and about 8.0. In certainembodiments, the physiological pH may be from about 7.3 to about 7.5,and may be about 7.4. For example, the buffering agent may be an 8.4%sodium bicarbonate solution. In these embodiments, for each cc of PRPisolated from whole blood, 0.05 cc of 8.4% sodium bicarbonate may beadded. In some embodiments, the syringe may be gently shaken to mix thePRP and bicarbonate.

As noted above, the PRP composition may comprise one or more additionalagents, diluents, solvents, or other ingredients. Examples of theadditional agents include, but are not limited to, thrombin,epinephrine, collagen, calcium salts, pH adjusting agents, materials topromote degranulation or preserve platelets, additional growth factorsor growth factor inhibitors, NSAIDS, steroids, anti-infective agents,and mixtures and combinations of the foregoing. In some variations, thePRP composition comprises one or more anti-arrhythmic agents.

Generally, anti-arrhythmic agents may be classified using the VaughanWilliams classification. In the Vaughan Williams classification, Class Idrugs operate by interfering with the sodium (Na+) channel and include,for example, quinidine, procainamide, disopyramide, lidocaine,phenytoin, mexiletine, tocainide, encainide, flecainide, indecainide,propafenone, and moricizine. Class II agents are beta blockers andinclude, for example, propranolol, esmolol, timolol, metoprolol,sotalol, and atenolol. Class III agents affect potassium (K+) efflux andinclude bretylium, amiodarone, sotalol, ibutilide, and dofetilide. ClassIV agents affect calcium channels and the AV node and include, forexample, verapamil and diltiazem. Class V agents work by other orunknown mechanisms and include, for example, moricizine, digoxin, andadenosine. Any suitable anti-arrhythmic drug and/or combination thereofmay be added to the PRP composition. The specific formulation used maybe determined based on, for example, the type of arrhythmia, patienthistory, drug interactions, or any other suitable factor.

Furthermore, the PRP compositions may comprise a contrast agent fordetection by an imaging technique such as X-rays, magnetic resonanceimaging (MRI), or ultrasound. Examples of such contrast agents include,but are not limited to, X-ray contrast (e.g., IsoVue), MRI contrast(e.g., gadolinium), and ultrasound contrast.

In some embodiments, as discussed above, the anti-arrhythmic agent maybe delivered to the patient mixed into the PRP composition. Additionallyor alternatively, the anti-arrhythmic agents may be delivered separatelyto the electrical conduction system or other tissues of the heart. Theanti-arrhythmic agent may be delivered via catheter prior to,simultaneously with, or subsequently to the PRP composition. Anysuitable doses of the anti-arrhythmic agent may be delivered at anysuitable intervals. Where one or more doses of an anti-arrhythmic agentor a combination thereof, the doses may be the same or may vary in termsof the agent selected and/or the amount of agent delivered. Some dosesmay include the PRP composition while others may not.

It should be understood that any suitable amount, mixture, and/orconcentration of anti-arrhythmic agents may be added to the PRP. Thetiming, amount, mixture, and/or concentration of the PRP composition maybe determined based on one or more patient characteristics, the type,and/or severity of the arrhythmia being treated, and/or any othersuitable factor. The anti-arrhythmic agents may be delivered to thepatient prior to, simultaneously with, and/or subsequently to deliveryof the PRP. In some embodiments, one or more anti-arrhythmic agents maybe mixed or otherwise combined with the PRP prior to delivery.

Devices and Methods

In some procedures, a PRP composition may be used as a non-specificarrhythmia treatment or arrhythmia prophylaxis. Thus, the specific typeand/or location of the arrhythmia may or may not be identified prior todelivery of the PRP composition to the patient. For example, it may beenough to simply determine that the patient has suffered from, or iscurrently suffering from, an arrhythmia. Thus, an ECG is not alwaysrequired in order to deliver the PRP. Of course, use of an ECG may bebeneficial in certain circumstances. For example, the amount of PRPcomposition prepared and used may vary, based upon the type ofarrhythmia. In some variations, whole blood is withdrawn prior torecording an ECG to begin preparation of the PRP composition. The ECGmay then be used to determine an appropriate delivery mechanismsimultaneously with the preparation of the PRP composition.

In some variations, the PRP composition is injected into a heart afterthe location, type, and severity of the arrhythmia (or some fractionthereof) has been identified. In certain instances, it may be helpful toidentify one or more discrete locations within the heart to deliver thePRP composition in order to increase the likelihood that the treatmentwill be effective. For example, to treat an arrhythmia identified as anatrial fibrillation, it may be helpful to deliver the PRP composition tothe SA node. Similarly, if the arrhythmia may be identified as aventricular tachycardia, it may be desirable to deliver the PRPcomposition to the AV node.

The location of the conductive tissue dysfunction may be determined orapproximated using various techniques. For example, in some variations,diagnostic procedures such as an electrophysiology study or anelectrical mapping study of the heart may be used. In other variations,one or more imaging technologies such as MRI, X-ray, CT scan, PositronEmission tomography (PET), Single Photon Emission Computed Tomography(SPECT), Electrical Impedance Tomography (EIT), Electrical SourceImaging (ESI), Magnetic Source Imaging (MSI), laser optical imaging andultrasound techniques may be used. Other technologies and approachesthat may be used include visual inspection during open chest surgicalprocedures, localized blood flow determinations, local electrical andstructural activity, nuclear cardiology, echocardiography,echocardiographic stress test, coronary angiography, magnetic resonanceimaging (MRI), computerized tomography (CT) scans, and ventriculography.

PRP compositions that are formulated as gels or other viscous fluids maybe difficult to deliver via a needle or syringe. Thus, in variationswhere the use of a needle or syringe is desirable, it may be desirableto add a gelling and/or hardening agent to the PRP composition in situ.One or more needles or catheters may be configured to deliver the PRPcomposition and/or the agent simultaneously, or substantiallysimultaneously, to the cardiac tissue. For example, if a needle is usedto deliver the PRP composition, the needle may comprise a plurality oflumens through which the PRP composition and the agent separatelytravel. Alternatively or additionally, separate needles may be used todeliver the components to the tissue at the same time or one after theother.

The PRP composition may be delivered minimally invasively and/orsurgically. For example, the PRP composition may be delivered to theheart using a catheter inserted into the patient via the femoral vein orartery, the internal jugular vein or artery, or any other suitable veinor artery. The PRP composition may be delivered along with one or moremedical devices, instruments, or agents to treat the arrhythmia and/orother cardiac conditions.

To deliver a PRP composition to the conduction system, a physician mayuse one of a variety of access techniques. These include surgical (e.g.,sternotomy, thoracotomy, mini-thoracotomy, sub-xiphoidal) approaches,endoscopic approaches (e.g. intercostal and transxiphoidal) andpercutaneous (e.g., transvascular, endocardial, and pericardial)approaches. Once access has been obtained, the composition may bedelivered via epicardial, endocardial, or transvascular approaches. Thecomposition may be delivered to the cardiac wall tissue or cardiacvessels in one or more locations. This includes intra-myocardial,sub-endocardial, and/or sub-epicardial administration.

Upon gaining access to the conduction tissues of the heart, the deliverydevice may be inserted through any appropriate vessel. The distal end ofthe delivery device may be then placed against the surface of theconduction tissues and one or more needles may be advanced into tissue.Following delivery of one or more components of the PRP composition, theneedles, if any, may be retracted. The delivery device may then berepositioned for additional delivery of one or more components of thecomposition or may be removed from the patient. Incisions may then beclosed using standard techniques.

In practice, the beating heart may be stabilized during the delivery ofthe PRP composition. For example, in some variations, the beating heartmay be slowed or stopped by delivery of one or more drugs and/or byelectrical stimulation of the heart. For example, a heart may bestabilized using pharmacologic asystole. Alternatively or additionally,a heart may be stabilized using pacing or other algorithms that renderthe heart fairly static. These procedures may initiate various cardiacstates such as reversible initiation of asystole, fibrillation, or aprolonged refractory state. In still other embodiments, mechanicalstabilization of the cardiac tissue may be achieved using any of avariety of mechanical stabilizing systems. In some examples, acombination of stabilizing procedures may be used.

The PRP composition may be delivered during a specific portion of thecardiac cycle, and in these variations, the use of one or morestimulation electrodes to act as a pacemaker during the delivery may bedesirable. For example, the beat-to-beat period may be artificiallylengthened so as to deliver the PRP composition during a specific phaseof the cardiac cycle. In these variations, the delivery device mayinclude one or more stimulation and/or sensing electrodes. For example,sensing electrodes may be used to sense contractions of the heart,thereby allowing the delivery of composition to be timed with cardiaccontractions. It may be desirable to deliver one or more components ofthe PRP composition between contractions of the heart.

In some examples, one or more cardiac sensors may be used during thetreatment procedures. The sensors may be any suitable sensor system(e.g., an electrical sensor, a chemical sensor, a pressure sensor, anintravascular imaging sensor, or a biosensor) capable of detecting oneor more signals indicative of a cardiac contraction or heartbeat. Acardiac sensor may be used to monitor the electrical activity of theheart by picking up and amplifying electrical signals from the heart anddisplaying a visual output and/or providing an audio output. Forexample, the output may be displayed on a display interface. Thephysician may use this output to inject the needles and/or compositioninto the tissue at a specific point in the cardiac cycle. The cardiacsensor may be coupled to a cardiac stimulator to manipulate or controlthe cardiac rhythm.

In some variations, a nerve stimulator may be used to electricallymanipulate cardiac rhythm by stimulating the vagus nerve. Vagalstimulation may produce asystole (slowing or stopping of the heart).Once the vagal stimulation is stopped, the heart may return to a normalrhythm. Alternatively, the heart may be paced. Vagal stimulation, aloneor in combination with electrical pacing, may be used selectively andintermittently to allow a physician to perform delivery of one or morecomponents of the composition into a temporarily stopped heart.

Typically, vagal stimulation may slow or even prevent the heart fromcontracting. Following initial slowing or stopping of the heart, one ormore components of the PRP composition may be delivered to the heart.Following a brief interval of nerve stimulation while the delivery maybe performed, nerve stimulation may be ceased and the heart may beallowed to contract. A cardiac stimulator or pacemaker may be used tocause the heart to contract or the heart may be free to beat on its own.In some variations, one or more electrodes may be used for pacing theheart as desired. A processor may control both cardiac and nervestimulation. For example, a processor may cease nerve stimulation andautomatically begin cardiac stimulation.

The delivery system may deliver the components of the PRP composition ina prescribed ratio (e.g., a ratio of the PRP to the anti-arrhythmicagent). The prescribed ratio may be calculated beforehand or determinedon an ad hoc basis once delivery begins. To deliver the components inthe prescribed ratio, the delivery device may include one or more gearshaving a corresponding gear ratio, one or more lumens having aproportional lumen size, or any other suitable mechanism. Some deliverydevices may include one or more mixing chambers. The multiple componentsmay be delivered using separate delivery devices or may be delivered oneafter the other using the same delivery device.

The delivery devices may be advanced through a vessel adjacent to theconduction tissues to be treated. The PRP composition may be injecteddirectly into the conductive tissue using a needle and/or a needle-tipcatheter. The PRP composition may alternatively or additionally beinfused into the vessel.

When the PRP compositions are delivered using one or more catheters, anysuitable catheter may be used. For example, the catheters may includeone or more lumens and staggered or flush tips. The catheters mayinclude needles or other devices (e.g., imaging devices) located at thedistal end, and plungers or any other control located at the proximalend. The catheters and/or other delivery devices may have differentlysized lumens to deliver multiple components of the PRP composition inthe prescribed ratio. When catheters are used, a physician may navigateto the heart using one of the routes known for accessing the heartthrough the vasculature, including but not limited to navigation to aheart chamber for epicardial, endocardial, and/or transvascular deliveryof the PRP composition.

Endocardial delivery of the PRP composition may comprise accessing atreatment site, for example, in the left ventricle of a heart, using adelivery device advanced percutaneously in an anterograde approachthrough the superior vena cava or inferior vena cava into the rightventricle. The delivery device may be passed through the interatrialseptum into the left atrium and then into the left ventricle to reachtreatment site. Alternatively, the device may be advanced using atransseptal procedure, e.g., through the intraventricular septum intothe left ventricle. In another embodiment, the PRP composition may beinjected directly into the interventricular septum from the rightventricle. An alternative endocardial delivery method may compriseaccessing the treatment site using a delivery device advancedpercutaneously in a retrograde approach through the aorta into the leftatrium and then into the left ventricle.

Transvascular delivery of compositions may comprise passing the deliverydevice through the coronary sinus into the cardiac venous system via thecardiac veins and, if needed, leaving the veins by tracking throughmyocardial tissue. An alternative transvascular delivery methodcomprises accessing a treatment site through the aorta into a coronaryartery to reach treatment site.

The devices for injecting or delivering the PRP compositions (catheteror otherwise) may include cooled parts or other temperature controlmechanisms to keep the PRP composition at a desired temperature. Variousembodiments of delivery devices may include a cooled chamber, and/or anagitator mechanism in a PRP chamber or injection chamber to preventsettling or clumping of the PRP components. For example, in somevariations, the catheter or other delivery device has a cooled lumen orlumens for keeping the PRP composition cool during delivery. Thedelivery devices may additionally or alternatively include a mixingchamber for mixing the PRP composition prior to delivery. The PRPcomposition may also be stored in an agitating/vibrating chamber, or thephysician may agitate the PRP composition once inside the deliverydevice by tilting or otherwise manipulating the device.

A practitioner may make multiple deliveries into various locations usinga single device, make multiple deliveries into various locations usingmultiple devices, make a single delivery to a single location using asingle device, or make a single delivery to a single location usingmultiple devices. The deliver devices may include at least one reusableneedle or catheter. Some embodiments may include delivery devices havingan automated dosing system (e.g., a syringe advancing system). Theautomated dosing system may allow each dose to be pre-determined anddialed in (may be variable or fixed). In some embodiments, aniontophoresis device may be used to deliver the PRP composition into theconductive tissue.

The PRP composition may alternatively or additionally be coated on oneor more devices such as, for example, sutures, stents, screws, and/orplates. Anti-arrhythmia devices, such as pacemaker leads and automaticdefibrillators may also be coated, sprayed, or dipped into the PRPcomposition prior to, simultaneously with, or subsequently toimplantation.

It may be desirable to deliver the PRP composition to the conductiontissues while avoiding coincidental delivery to other cardiac tissues orother locations adjacent to the heart. For example, the PRP compositionmay gel or harden upon delivery to prevent migration. In somevariations, a balloon catheter may be placed in the coronary sinus andinflated during delivery until the PRP composition has solidified or atleast partially immobilized. Other variations may include a pressurecontrol system on the delivery device to prevent pressure-drivenmigration of the PRP composition. Backbleed may also be prevented bykeeping the needle in place for several seconds (e.g., about 5 to about30 seconds, or about 5 to about 120 seconds) following an injection.

Sensors may be used to direct the delivery device to a desired locationand/or to deliver the PRP composition. For example, real-time recordingof electrical activity (e.g., an ECG), pH, oxygenation, metabolites suchas lactic acid, CO₂, or the like may be used. The sensors may be one ormore electrical sensors, fiber optic sensors, chemical sensors, imagingsensors, structural sensors, and/or proximity sensors that measureconductance. The sensors may be incorporated into the delivery device orbe separate from the delivery device. In some embodiments, the sensorsmay sense and/or monitor such things as needle insertion depth, bloodgas, blood pressure or flow, hemocrit, light, temperature, vibration,voltage, electric current, power, and/or impedance. The sensors mayinclude one or more imaging systems and may be coupled to anyappropriate output device, for example, a LCD or CRT monitor whichreceives and displays information.

The total volume of the PRP composition delivered to the patient may bebased on the size of the heart, the amount of the affected conductivetissue, and/or the desired outcome of the procedure. For example, thetotal volume of composition injected may be less than 15000 μL.

The number of delivery sites in the heart may be based on the type andlocation of the arrhythmia(s), the desired location of the PRPcomposition, and the distance separating the desired locations. Thenumber of delivery sites may range from about 1 to about 25 sites. Thedistance separating delivery sites may vary based on the desired volumeof platelet gel to be delivered per delivery site, the desired totalvolume to be delivered, and/or the condition of the conductive tissue.At the delivery site, the PRP composition may be injected, infused, orotherwise disposed at or adjacent to the conductive tissue. The PRPcomposition may also be infused into the vasculature (i.e., vessels)upstream of the target site, so that it will flow towards the affectedconduction tissue.

The location of the delivery sites may vary based on the size and shapeof the affected conductive tissue, and the desired extent of thetreatment of the tissue. For example, the PRP composition may bedelivered into the affected conductive tissue, and/or into the tissuethat bordering the affected conductive tissue. Similarly, thecomposition may be delivered to any combination of the regions ofconductive tissue and other cardiac tissue.

In some instances, selective infusion of a PRP composition may be lessarrhythmogenic than needle injection of a PRP composition directly intothe myocardium. FIG. 2 is a schematic illustration of the cardiacvasculature (200). The cardiac vasculature (200) comprises, for example,the right coronary artery (202), the acute marginal artery (204), theposterior descending artery (206), the left main coronary artery (208),the circumflex artery (210), the left anterior descending artery (212),the diagonal artery (214), and the obtuse artery (216). Certainarrhythmias may affect include aberrant pathways or foci that areperfused by certain branches of the cardiac vasculature. For example,branches of the right coronary artery (202) provide the blood supply tothe AV node in about 90% of patients. Thus, selective access to theright coronary artery (202) may be used to treat abnormalities of the AVnode. In another example, certain accessory tracts ofWolff-Parkinson-White syndrome affecting the upper ventricles may betreated by accessing the circumflex artery (210).

The timing of PRP delivery relative to an arrhythmic event may be basedon the severity of the arrhythmia, the extent of the arrhythmia, thecondition of the patient, and the progression of any concurrentarrhythmia treatments. The PRP composition may be delivered at anysuitable time. For example, it may be delivered immediately after theonset of an arrhythmia, within one hour of an arrhythmia, one to eighthours following an arrhythmia, or three to four days after an arrhythmiaafter clinical stabilization of the patient when it is safer for thepatient to undergo a separate procedure. The timing may be based uponthe onset and/or the cessation of the arrhythmia. In some variations,the composition is delivered about one week, about 1 to about 3 weeks,about 1 to about 6 months, or even up to or more than about 1 year afterthe arrhythmia. Other times for injecting compositions into theconductive tissue are also contemplated, including prior to anyanticipated arrhythmia, and immediately upon finding an area ofconductive tissue responsible for one or more arrhythmias (forpreventing additional arrhythmias). Of course, compositions may beinjected into the conductive tissue years after an arrhythmia.

Alternatively or additionally, the PRP composition may be usedprophylactically, e.g., with certain conditions associated with anincreased arrhythmia risk or with episodic arrhythmias. For example, thePRP composition may be delivered one hour, thirty minutes, 15 minutes, 5minutes, or just prior to or during a procedure associated with aheightened arrhythmia risk (e.g., a reperfusion procedure). To treatepisodic arrhythmias, the PRP composition may be used after an episode,when an arrhythmia occurs, or before an arrhythmia is likely to occur.

In some variations, as discussed above, one or more anti-arrhythmicagents may be delivered to the patient mixed into the PRP composition.Additionally or alternatively, the anti-arrhythmic agents may bedelivered separately to the electrical conduction system of the heart.The anti-arrhythmic agent may be delivered via catheter prior to,simultaneously with, or subsequently to the PRP composition. Anysuitable doses of the anti-arrhythmic agent may be delivered at anysuitable intervals. Where one or more doses of an anti-arrhythmic agentor a combination thereof, the doses may be the same or may vary in termsof the agent selected and/or the amount of agent delivered. Some dosesmay include the PRP composition while others may not.

In some embodiments, the PRP composition may be inhaled using, forexample, an inhaler or a nebulizer. To deliver the PRP composition inpowder form using, for example, an inhaler, the PRP composition may bedried once it may be prepared as described above according to knownpharmaceutical techniques.

The devices and methods may be used in conjunction with currentanti-arrhythmia therapies and/or concurrently with other medicalprocedures that are generally known to increase the likelihood of anarrhythmia. For example, and as discussed generally with respect to themethods and devices, various cardiac procedures may require slowing(bradycardia) and/or stopping (asystole) the heart for a period of time.

The PRP composition may be incorporated into an Advanced Cardiac LifeSupport (ACLS) protocol for treating acute cardiac arrhythmias. The ACLSprotocol comprises one or more procedures for treating a patient basedon a type of arrhythmia. The ACLS protocol comprises first establishingand securing an airway device (e.g., an Endotracheal Tube (ETT),Laryngeal Mask Airway (LMA), Cuffed Oropharyngeal Airway (COPA),Combitube, etc.) then ventilating with 100% oxygen gas and confirmingthe airway placement (e.g., exam, ETCO₂, and SpO₂). The rhythm and pulsemay be evaluated. The medical personnel continues CPR, obtains IVaccess, and gives rhythm-appropriate medications according to specificalgorithms based on the type, location, and severity of the arrhythmia.

In some instances, a cardioversion may be performed during ACLS or as anelective procedure to treat an arrhythmia. A cardioversion is a briefelectrical shock to the heart to shock the heart into a normal rhythm.The initial cardioversion may comprise three shocks that may besynchronized to the arrhythmic heart beat. The shocks may be performedin increasing energy levels. For example, the first shock may be at 100Joules, the second shock may be at 200 Joules, and the third shock maybe at 300 Joules. The PRP composition may be delivered to the heartprior to, in between, and/or subsequently to the three shocks. In someinstances, more than one dose of the PRP composition may be deliveredduring the cardioversion. In some embodiments (e.g., if the cardioversion stabilizes the patient), whole blood may be withdrawn from thepatient following the cardioversion for production of PRP composition tobe delivered to the patient.

In the event of a ventricular tachycardia, a cardioversion may beperformed, especially if the heart rate is greater than 150 beats perminute or where signs of hemodynamic instability are present. Before orafter the cardioversion, the patient may also be treated using one ormore anti-arrhythmic agents and/or PRP compositions. The,anti-arrhythmic agent and/or the PRP composition may be selected basedon the morphology of the tachycardia and/or the ejection fraction (EF)of the heart. For example, if the tachycardia is monomorphic and the EFis normal, arrhythmic agents such as procainamide and sotalol may bedelivered. Alternatively, arrhythmic agents such as amiodarone andlidocaine may be administered. If, however, the EF is lower than normal,amiodarone or lidocaine may be administered over an IV and anothercardioversion may be performed.

In instances where the ventricular tachycardia is polymorphic, thetreatment may be selected based on the QT interval indicated by an ECG.If the QT is normal, the treatment selected may be depend on the EF ofthe heart. When the EF is normal, the anti-arrhythmic agent used may bea betablocker such as sotalol, and/or another agent including, but notlimited to, lidocaine, amiodarone, and procainamide. When the EF isbelow normal, delivery of amiodarone or lidocaine may be synchronizedwith one or more cardioversion. If however, the QT interval is prolonged(i.e., torsades de pointes), the PRP composition may be delivered withand/or include magnesium, isoproterenol, phenytoin, and/or lidocaine. Insome instances, the heart may be treated using overdrive pacing.

The PRP composition may also be delivered as disclosed herein during orafter a bradycardia (i.e., slow heart beat). In these instances, the AVnode may be blocking the impulse from propagating into the ventricles.To treat a bradycardia, atropine (e.g., 0.5-1.0 mg IV push q 3-5 min upto a maximum of 0.04 mg/kg), dopamine (e.g., 5-20 μg/kg/min), and/orepinephrine (e.g., 2-10 μg/min) may be administered. In these instances,transcutaneous pacing (TCP) may be performed if the bradycardia issevere.

In the event of atrial fibrillation or atrial flutter, the ACLS protocolcomprises performing a cardioversion and administering one or moreanticoagulants. The cardioversion may occur immediately or later as anelective cardioversion. Cardioversions may also be performed chemicallyusing anti-arrhythmic drugs. In these embodiments, the PRP compositionsmay not include a clotting agent. Examples of anti-coagulants may beselected based on ejection fraction (EF). If the patient has a normalEF, a calcium blocker or a beta blocker to control the heart rate may beadministered. Some anti-arrhythmic agents that may be used includeamiodarone, ibutilide, procainamide, flecainide, propafenone, andsotalol. If the patient has an EF of less than 40% and/or congestiveheart failure (CHF), the heart rate may be controlled by administeringdigoxin, diltiazem, and/or amiodarone. In the case ofWolff-Parkinson-White syndrome characterized by a short PR interval andlong QRS interval with a delta wave associated with paroxysmaltachycardia, amiodarone, procainamide, propafenone, sotalol, orflecainide may be administered.

In general, the ACLS protocol may be performed by alternating electricalshocks with administration of drugs while monitoring the heart rateusing an ECG. The PRP composition may generally be administered with oneor more other anti-arrhythmia and/or anti-coagulant drugs. Apre-prepared PRP may be used in emergency situations while an autologousPRP may be used after the patient is stabilized, for example, inconjunction with an elective cardioversion.

The PRP composition may also be used in an electrophysiology study(e.g., a cardiac electrical mapping study, with or without an ablationtreatment) where the conduction system may be evaluated for abnormalconduction pathways or foci, and where portions of conductive tissue maybe ablated to treat the abnormal impulse propagation. Ablation may beused, for example, in patients with Wolff-Parkinson-White syndrome orany of a variety of other arrhythmias, including those caused by reentryor automaticity, for example. The electrophysiology study may be used todetermine the pathological conduction pathways and to ablate them. ThePRP may be delivered before, during, and/or after the electrophysiologystudy to stabilize or otherwise treat the aberrant pathways.

In some variations, as briefly described above, the PRP composition maybe used in conjunction with a procedure to deliver one or more implantsto the heart. Some of these procedures may be associated with acuterisks of arrhythmia or exacerbate existing arrhythmias. The implants maybe devices for treating a chronic arrhythmia or to treat other medicalconditions. Examples of implant procedures include implantation and/orremoval of pacemakers and automatic defibrillator leads. The PRPcomposition may be delivered prior to, simultaneously with, and/orsubsequently to, the placement of leads in the conduction tissues of theheart. In one example, a patient undergoing implantation of a cardiacrhythm management device may be pre-treated with a PRP composition aboutfrom about 1 to about 4 hours or more before the procedure, sometimesabout 1 to about 2 days before, and other times about 1 week or morebefore. The PRP composition may have an additional desirable effect bypromoting fibrous tissue growth to anchor the leads. In some variations,the leads, devices, or other implants (e.g., sutures) are coated withthe PRP composition.

The PRP composition may be delivered at any suitable dose. In someembodiments, the dose may be between about 1 cc and about 3 cc, betweenabout 3 cc and about 5 cc, between about 5 cc and about 10 cc, betweenabout 10 cc and about 20 cc, or more. The dose may be deliveredaccording to a medical procedure (e.g., at specific points in aprocedure) and/or according to a schedule. For example, prior to anelective cardioversion, the PRP composition may be delivered about 24hours, about 12 hours, about 6 hours, about 2 hours, and/or about 1 hourbefore the procedure begins. A portion of the dose and/or an additionaldose may be delivered during the elective cardioversion (e.g.,immediately before the initial shock, between shocks, and/or immediatelyafter the final shock). One or more doses of the PRP composition may bedelivered after the elective cardioversion and/or on an as needed basis.

As mentioned previously, a PRP composition may additionally oralternatively be used to prevent and/or treat arrhythmias that may occurduring other cardiac procedures. Cardiac procedures may includeanti-arrhythmia procedures, procedures to correct congenital heartdefects, or other pathologies. Examples of other cardiac proceduresinclude, but are not limited to, angioplasty, coronary artery bypass,Minimally Invasive Direct Coronary Artery Bypass (MIDCAB), off-pumpcoronary artery bypass, Totally Endoscopic Coronary Artery Bypass(TECAB), aortic valve repair, aortic valve replacement, mitral valverepair, mitral valve replacement, Ross procedure, Bentall procedure,pulmonary thromboendarterectomy, valve-sparing aortic root replacement,cardiomyoplasty, Dor procedure, heart transplantation, septal myectomy,ventricular reduction, pericardiocentesis, pericardiectomy, atrialseptostomy, Blalock-Taussig shunt procedure, Fontan procedure, Norwoodprocedure, Rastelli procedure, Maze procedure (Cox maze and minimaze),and/or pacemaker insertion. The PRP composition may used to prevent anarrhythmia associated with reperfusion of the cardiac tissue during anyof the above procedures. As is known, reperfusion may cause aspontaneous arrhythmia to occur after cardiac surgery.

In some embodiments, the PRP composition may be delivered to preventand/or treat an arrhythmia resulting from an electrolyte imbalancecaused by, for example, kidney failure. In kidney failure, electrolytelevels essential to the proper running of cardiac conduction system(e.g., calcium, potassium, sodium, magnesium, etc.) may be improperlymanaged. The resulting electrolyte balance may prevent the conductiontissues from propagating the impulse normally.

The PRP composition may also be used in the placement of a single lumenpulmonary artery catheter or a Swan-Ganz catheter. The Swan-Ganzcatheter may be advanced through the superior vena cava to the pulmonaryartery. Because the Swan-Ganz catheter passes through the right atriumand the right ventricle, where Koch's Triangle is located, there is aheightened risk of arrhythmia. To prevent or treat an arrhythmia, thePRP may be delivered prior to, simultaneously with, and/or subsequentlyto, the placement of the Swan-Ganz catheter. In some embodiments, theSwan-Ganz catheter may be coated with the PRP. The PRP composition mayalso be delivered periodically while the Swan-Ganz catheter is in place.

In some embodiments, the PRP composition may be delivered to the patientbased on the mechanism of the arrhythmia. As discussed herein, anarrhythmia may be caused by one or more mechanisms includingautomaticity, triggered activity, pre-excitation and/or re-entry. Thesemechanisms may correspond to one or more cardiac pathologies aside fromthe arrhythmia itself.

An arrhythmia may be caused at least in part by abnormalities inautomaticity, i.e., an abnormal spontaneous polarization, of the cardiactissues. Automaticity normally originates in the SA node and propagatesthrough the rest of the conduction system. However, abnormalities maycause a portion of the conduction tissues to depolarize out of sync withthe rest of the conduction system. Automaticity may arise, for example,when the conduction of the impulse from the SA node is blocked.

Triggered activity typically occurs when the ion channels in individualheart cells are damaged, blocked, or otherwise altered resulting inabnormal propagation of the impulse. In some instances, triggeredactivity can lead to sustained abnormal rhythm and may be a result ofanti-arrhythmic drugs.

Pre-excitation can occur when accessory or bypass tracts providealternate conduction pathways for myocardial depolarization. Forexample, these accessory or bypass tracts may bypass the AV node,resulting in premature depolarization of the ventricular muscle. In someinstances, the premature depolarization wave may merge with thedepolarization wave from the normal conduction pathway, resulting in afusion beat or wave.

Re-entry is another possible mechanism that may be used to characterizean arrhythmia. Typically, the impulse is conducted through theconduction system in a uniform fashion from the SA node to the AV nodeto the Purkinje fibers to depolarize each in turn. However, if a portionof the conduction tissue is too slow or too quick to depolarize, theconduction tissues that normally depolarize in response may depolarizemore than once in a single cardiac cycle. For example, the conductiontissues may depolarize first in response to the original impulse andthen quickly depolarize again in response to the delayed impulse.Re-entry is associated with several types of arrhythmias including, forexample, atrial flutter, supraventricular tachycardia, ventriculartachycardia and fibrillation arrhythmias.

In some examples, a PRP composition may be used to treat a patientdiagnosed with an acute myocardial infarction. Treatment with the PRPcomposition may occur in the field or in the emergency room setting.Criteria for PRP composition treatment may include positive cardiacmarkers, ST-elevations, or new wall motion abnormalities identified onechocardiogram, for example. The decision to treat with a PRPcomposition, and the treatment location(s), may depend upon one or morecharacteristics of the myocardial infarction. For example, a myocardialinfarction may be characterized as a ST-elevation myocardial infarction(STEMI) or non-ST-elevation myocardial infarction (NSTEMI), a Q-wave ornon-Q-wave myocardial infarction, and whether they are subendocardial ortransmural. Myocardial infarctions may also be characterizedanatomically by cardiac wall region and/or the suspected blockage sitein the cardiac vasculature. Myocardial infarctions may also becharacterized as anterior, lateral, inferior, posterior, septal, orright-ventricular in location, and may involve disease or blockage ofthe left-anterior descending, left circumflex, left main,posterior-descending and right coronary arteries, for example.

In other examples, timing of the PRP composition treatment may be basedupon other treatments that are indicated in a patient with a myocardialinfarction. In some instances, a PRP composition may be deliveredbefore, during, and/or after reperfusion therapy is performed to treatan acute myocardial infarction or a previous myocardial infarction.Reperfusion therapies may include thrombolytic therapy, angioplasty,stenting (including bare metal stents and drug-eluting stents) orcoronary artery bypass graft (CABG) surgery. In some instances,reperfusion therapy may be associated with an increased risk of anarrhythmia, including sudden death. Also, it is believed that theetiology of reperfusion arrhythmias or reperfusion arrhythmia risk maybe different from the arrhythmia etiologies associated with themyocardial infarction itself. For example, some reperfusion arrhythmiasmay be caused by triggered activity and/or re-entry. A PRP compositionmay be prepared before or at the start of a reperfusion procedure, butnot used unless an arrhythmia occurs during the procedure. In otherreperfusion procedures, the patient may be prophylactically pre-treatedwith a PRP composition before reperfusion occurs, e.g., before guidewirepassage across an occlusion, stent positioning, stent expansion, orreestablishment of coronary flow through a bypass segment.

Kits

Kits may include any device, component, or combination of devices and/orcomponents described herein. For example, the kits may include one ormore preparation devices, one or more delivery devices, one or morecollection devices, and/or instructions for use. The one or morepreparation devices may be for preparing PRP and may comprise acentrifuge, for example. The one or more delivery devices may beconfigured to deliver a PRP composition comprising the PRP to a regionof the heart to treat a cardiac arrhythmia. The one or more collectiondevices may comprise one or more syringes, apheresis needles, or otherdevices for collecting blood from a patient. The patient may bepresently suffering or have suffered a cardiac arrhythmia. Thecomponents of the kit may be packaged in sterile containers. The kitsmay comprise one or more single-use components. Instructions may be inwritten or pictograph form, or may be on recorded media including audiotape, audio CD, video tape, DVD, CD-ROM, or the like.

The kits may be designed to target specific cardiac arrhythmias. In onevariation, a kit may be designed for use with a ventricular tachycardia.Such a kit may include, for example, one or more collection devices, ECGleads, and/or one or more anti-arrhythmic agents.

In addition to the foregoing uses for the compositions, methods andsystems described herein, it will be apparent to those skilled in theart that other injured tissues, in addition to injured cardiac tissue,would benefit from the delivery of structural support materials to treatthe injuries. Non-limiting examples of such tissues include the stomach,to reduce food intake and increase satiety; the abdominal wall, toprevent and treat hernias and the bladder to prevent or treatincontinence. Such tissues may additionally include vascular tissues.

Examples Example 1

PRP was prepared using a centrifuge unit made by Harvest (Plymouth,Mass). (Similar units are available as The Biomet GPS system, the DepuySymphony machine and the Medtronic Magellan machine.) Approximately 55cc of blood was drawn from the patient using a standard sterile syringe,combined with 5 cc of a citrate dextrose solution for anticoagulation,and then spun down to isolate the platelets according to themanufacturer's protocol. These platelets were then resuspended inapproximately 3 cc of plasma. The resulting platelet rich plasmasolution (PRP) was quite acidic and was neutralized with usingapproximately 0.05 cc of an 8.4% sodium bicarbonate buffer per cc of PRPunder sterile conditions to approximately physiologic pH of 7.4. The PRPwas not activated through addition of exogenous activators. This PRPcomposition is referred to herein as autologous platelet extract (APEX).

Example 2 Cardiac Muscle

Adult female mice (n=19) underwent left anterior descending (LAD) arteryligation (45 minutes) followed by 5 minutes reperfusion to mimicmyocardial infarction. An APEX composition was prepared as described inExample 1 The extract was not activated through the addition ofexogenous agent(s).

Unactivated PRP (n=10) or saline (n=9) was injected into murinemyocardium. Three weeks later MRI was used to evaluate ejectionfraction.

The data is shown in FIG. 1. PRP improves cardiac function by 28% (asmeasured by Left Ventricular Ejection Fraction) relative to control at 3weeks after a heart attack. The data is statistically significant atp=0.04. This data supports the use of PRP in an ischemia-reperfusionheart model.

Example 3 Treatment of a Reperfusion Arrhythmia in an Animal Model

Arrhythmias frequently occur when ischemic cardiac tissue is reperfusedwith blood. This can occur in a variety of situations; however the mostcommon is following an acute myocardial infarction. Typically, whenblood flow is successfully reestablished after a coronary artery hasbeen blocked, reperfusion arrhythmias can occur. These arrhythmias areusually in the form of ventricular ectopy including, but not limited to,non-sustained ventricular tachycardia, sustained ventricular tachycardiaand ventricular fibrillation. These arrhythmias can result inhemodynamic compromise and, in some cases, death.

The successful test of PRP in an animal model simulating a reperfusionarrhythmia following an acute myocardial infarction was conducted asfollows: In a 40 Kg swine, the left anterior descending artery wasidentified using coronary angiography and then occluded with anangioplasty balloon (thus mimicking a myocardial infarction).Hemodynamic and electrocardiographic measurements were recorded duringthe procedure. After sixty minutes of arterial blockage, the balloon wasdeflated resulting in reperfusion. This led to pronounced ventricularectopy in the form of ventricular couplets, triplets, and non-sustainedventricular tachycardia.

Following 30 minutes of catheter-based endocardial ventricular mapping,ventricular arrhythmias persisted even without a catheter in place andcontinued while an injection catheter was placed into the left ventriclecavity. Platelet rich plasma (PRP) was then injected into myocardialregion of the acute occlusion in an attempt to improve cardiac function.Five minutes after ten injections of 0.2 ml of PRP under fluoroscopicguidance, the cardiac rhythm returned to a normal sinus pattern withoutany ventricular ectopy.

FIGS. 4 a and 4 b depict EKG tracings taken of the test subject beforeand after treatment with the PRP. FIG. 4 a, recorded prior to the PRPtreatment, shows a highly irregular pattern consistent with multifocalpremature ventricular contractions consistent with ischemia and recentreperfusion. The fact that the QRS complexes are of different shapesindicates that pacing is occurring from multiple sites in the myocardiumin a disorganized manner and thus indicates a serious disruption in theheart's normal pacemaking. FIG. 4 b shows an EKG taken following PRPtreatment and shows that the rate and rhythm have normalized.

FIG. 4 c shows a ventricular pressure measurement as measured usingcardiac catheterization. The relatively low pressures show that theventricles are unable to generate sufficient pressures to pump bloodefficiently during the arrhythmia as they are contracting in anirregular and disorganized manner. By contrast, the pressures recordedunder FIG. 4 d are much higher. This reflects that the myocardium isable to fill and contract properly so as to function effectively.

Example 4 Treatment of Acute Coronary Syndrome with PRP

A patient presents with symptoms of myocardial ischemia such as chestpain. The diagnostic evaluation including a physical exam, EKG, as wellas laboratory studies determines that the patient is having acutecoronary syndrome such as unstable angina, Non-ST elevation myocardialinfarction, or ST elevation myocardial infarction. A blood sample isdrawn to create platelet rich plasma. The patient is taken to thecatheterization laboratory to perform reperfusion therapy and then haveplatelet rich plasma applied, injected, or instilled to improve cardiacrhythm or protect against reperfusion arrhythmia. In another embodiment,the patient would go to the catheterization laboratory to have PRPeither injected or instilled in a delayed manner to prevent futurearrhythmia.

The PRP in the above example can be prepared using a variety oftechniques including, but not limited to, centrifuges, gravityfiltration devices, cell sorting or others. It can be combined with stemcells, genetic engineering or mechanical devices such as permanent orbioaborbable pacemaker or stent. The PRP can be autologous or made fromallogenic sources. It can be made and then stored in a frozen orlyophilized state to be applied to the tissue later. In a preferred formit would be buffered to physiologic pH but it may also be valuable toinstill PRP at either acidic or basic pH for specific clinicalindications such as ablation of an abnormal conduction pathway. In yetanother embodiment, the PRP could be prepared in a form that is depletedof neutrophils or other fractions of white blood cells either partiallyor completely.

Example 5 Treatment of Arrhythmia using the PRP Formulation from Example4

A patient presents with symptoms of palpitations, lightheadedness andpre-syncope or syncope. A diagnostic evaluation including physical examand EKG determines that the patient is in a sustained or non-sustainedarrhythmia such as, but not limited to, supraventricular or ventriculartachycardia. The patient is treated at the bedside or taken to thecatheterization laboratory to have PRP injected or instilled into thelocation of the arrhythmia as located by topographic electrocardiogramor catheter-based electrophysiology study.

Example 6 Treatment of Reperfusion Arrhythmia using the PRP Formulationfrom Example 4

PRP can be used to prevent arrhythmia associated with reperfusion inischemic myocardial tissue. A patient who is undergoing cardiac surgeryrequiring bypass support such as, but not limited to, coronary arterybypass grafting, valve repair, valve replacement, cardiactransplantation, or other cardiac surgeries can have PRP injected orinstilled into the myocardial tissue prior to, during, or afterreperfusion. Repe rfusion occurs when coming off the bypass machine.Injection is performed using needle injection under direct visualizationor via a catheter placed into the heart under image guidance. The PRP isadministered via single or multiple injections.

Example 7 Treatment of Bradycardia using the PRP Formulation fromExample 4

Bradycardias are usually the result of poor signal generation by cardiacpacing tissue or by abnormalities within conduction tissues. When thenormal pacing system fails, the heart relies on various accessorypacemakers that beat at a slower rate than the SA node. This is oftenassociated with increasing patient age as well as with histologicalevidence of fibrosis of the tissues involved. One such example is “sicksinus syndrome,” a disorder that results in the development ofsignificant bradycardia and the need for an implantable pacemakingdevice.

Patients with bradycardia can present with lightheadedness, near-syncopeor full syncope. The diagnosis can be established using an EKG or arhythm monitor. Once identified, early treatment to prevent furtherprogression of the disease can result in avoiding the need for animplantable electrical pacemaker. Treatment with PRP reduces furtherfibrotic changes to the cardiac tissue and reduces local inflammationthus improving the generation of an impulse signal thus preventing theworsening of the bradycardia.

A patient presents with symptoms of syncope. History, physicalexamination and EKG result in a diagnosis of likely sick sinus syndrome.The patient then undergoes an electrophysiology study in thecatheterization laboratory to “map” the electrical conduction of the SAnode and the refractory period using a specialized catheter positionedin the right atrium under flourscopic visualization. Once identified, asecond catheter with a small injection catheter on the tip is positionedon the same tissue as the signal sensor and platelet rich plasmainjected into the location via an endomyocardial technique. Since thisinjection can result in temporary inability to produce a pacing signalfrom the SA node, the sensor catheter has the ability to pace the heartat a backup rate sufficient to support systemic hemodynamics. Thisprocedure is performed once or multiple times to produce the desiredeffect of improving the patient's cardiac rhythm. Proof of improvementis measured via EKG or other diagnostic device or method.

Example 8 Treatment of a Patient with Heart Block Using the PRPFormulation from Example 4

A patient presents with symptoms of syncope. History, physicalexamination and EKG result in a diagnosis of a disruption in the cardiacconduction system at the level of the AV node (“heart block”). Asubsequent electrophysiology study performed in the catheterizationlaboratory identifies the location of the disruption on the conductionsystem. While one monitor with pacing ability monitors the heart rate, asecond catheter with a small injection catheter on the tip is positionedat the site of the conduction abnormality and platelet rich plasma isinjected into the location via an endomyocardial technique one or moretimes. The resolution of the heart block is assessed via EKG or otherdiagnostic method.

Example 9 Treatment of Myocardial Tissue to Reduce Threshold andIncrease Battery Life for Pacing

Bradycardias are often treated by the placement of a permanentpacemaker. Such devices provide electrical stimulation of the myocardialconductive tissue using leads that are in contact with the epicardial orendocardial surface of the heart. “Myocardial capture” is achieved bydelivering a capture signal capable of stimulating myocardial tissue.Myocardial fibrosis can necessitate higher pacing voltages to achievecapture. Damage to cardiac tissue from the pacemaker leads themselvescan result in local fibrosis, thus necessitating higher pacing voltagesand thereby reducing pacemaker battery life. Treatment with PRP canreduce the progression of fibrosis or even reduce existing fibrosis.This can minimize the energy consumption of the pacemaker and extendbattery life.

A patient presents with symptomatic bradycardia that requires theplacement of a permanent pacemaker (PPM). PRP is injected or instilledinto the myocardial region wherein the pacemaking lead or patch isattached to the endocardial or epicardial surface. This is performedbefore, during or after the placement or attachment of the lead orpatch. In one embodiment, an injection catheter is used to direct theinjection of PRP into the region wherein the active fixation lead is tobe attached. This can be performed in the catheterization laboratoryunder fluoroscopic guidance, with the endocardial injection occurringprior to, during or after the fixation of the lead. In an alternativeembodiment, the patient is in the operating room for placement of aepicardial patch for pacing. The patient would have PRP injected orinstilled into the location of the epicardial patch before, during orafter the placement of the patch for pacing. In yet another embodiment,PRP is delivered via intramuscular injection or via a transdermal patchto enhance cardiac function or improve cardiac rhythm. In all of theseembodiments the goal is to reduce fibrosis and enhance electricalconductivity. Treatment of myocardial tissue with PRP can facilitatefunctional pacing in the heart, reduce conduction resistance fromfibrosis, and thereby reduce the energy requirements for the pacemakerand ultimately extend its battery life.

Example 10 Treatment of Myocardial Tissue to Reduce the DefibrillationThreshold and Energy Requirements of Defibrillation Devices

Patients with various conditions including coronary artery disease,ischemic or non-ischemic cardiomyopathy or a history of ventriculararrhythmias can have an implantable cardiac debribrilator (ICD) placedto treat a life-threatening arrhythmia if and when they arise. Patientswith cardiomyopathy often have myocardial fibrosis which increasesresistance and necessitates a higher electrical charge to defibrillatethe ventricle. PRP can be used to treat the fibrosis either prior to,during, or after the placement of an ICD. PRP can also be used in thetreatment of patients undergoing heart transplant or valve surgery toimprove rhythm or function.

A patient is diagnosed with ischemic cardiomyopathy and his doctorsrecommend that he have an ICD. Prior to ICD placement, the cardiactissue in the area where the leads of the ICD are to be placed isinjected or infused with PRP. Local fibrosis is reduced thus enablingthe ICD to operate at a lower voltage when activated. This extends thebattery life of the ICD.

While methods, devices, and kits have been described in some detail hereby way of illustration and example, such illustration and example may befor purposes of clarity of understanding only. It will be readilyapparent to those of ordinary skill in the art in light of the teachingsherein that certain changes and modifications may be made theretowithout departing from the spirit and scope of the appended claims.

1. A method for treating a cardiac conduction abnormality, comprising:identifying a cardiac conduction abnormality in a patient; anddelivering a platelet rich plasma composition to the patient in anamount sufficient to treat the conduction abnormality.
 2. The method ofclaim 1, wherein the conduction abnormality comprises a cardiacarrhythmia.
 3. The method of claim 1, wherein the patient has a negativecardiac enzyme elevation.
 4. The method of claim 1, further comprisingmonitoring the conduction abnormality after delivering the platelet richplasma composition.
 5. The method of claim 1, wherein delivering theplatelet rich plasma composition comprises delivering the platelet richplasma composition via a minimally invasive procedure.
 6. The method ofclaim 5, wherein delivering the platelet rich plasma compositioncomprises delivering the platelet rich plasma composition using acatheter.
 7. The method of claim 5, wherein delivering the platelet richplasma composition comprises preparing an inhalable form of the plateletrich plasma composition and providing the inhalable form to the patient.8. The method of claim 1, wherein delivering the platelet rich plasmacomposition comprises delivering the platelet rich plasma compositionvia a surgical procedure.
 9. The method of claim 1, wherein the plateletrich plasma composition may be prepared from whole blood of the patient.10. The method of claim 9, wherein the whole blood is withdrawn from thepatient during a cardiac arrhythmia.
 11. The method of claim 1, whereinthe conduction abnormality comprises a bradycardia.
 12. The method ofclaim 1, wherein the conduction abnormality comprises a tachycardia. 13.The method of claim 1, wherein the conduction abnormality is ventriculartachycardia.
 14. The method of claim 1, wherein the conductionabnormality is ventricular fibrillation.
 15. The method of claim 1,wherein the conduction abnormality us caused at least in part byautomaticity.
 16. The method of claim 1, wherein the conductionabnormality is caused at least in part by a reentry pathway.
 17. Themethod of claim 1, wherein the conduction abnormality is chronic. 18.The method of claim 1, wherein the conduction abnormality is acute. 19.The method of claim 1, wherein the conduction abnormality is episodic.20. The method of claim 1, wherein the platelet rich plasma compositionis buffered to a physiological pH.
 21. The method of claim 20, whereinthe physiological pH is between about 7.3 and about 7.5.
 22. The methodof claim 1, wherein the amount sufficient to treat the cardiacarrhythmia is about three to about five cubic centimeters of theplatelet rich plasma.
 23. The method of claim 1, wherein determining acardiac arrhythmia exists comprises using an electrocardiogram.
 24. Themethod of claim 23, wherein the electrocardiogram is recorded using aHolter monitor or a cardiac event monitor.
 25. The method of claim 1,wherein the platelet rich plasma composition is delivered to or adjacentto a sino-atrial node.
 26. The method of claim 1, wherein the plateletrich plasma composition is delivered to or adjacent to anatrioventricular node.
 27. The method of claim 1, wherein the plateletrich plasma composition is delivered to or adjacent to the Purkinjefibers.
 28. The method of claim 1, wherein the platelet rich plasmacomposition comprises an anti-arrhythmic agent selected from the groupconsisting of a sodium channel blocker, a beta blocker, a potassiumchannel blocker, and a calcium channel blocker.
 29. The method of claim1, further comprising preparing the platelet rich plasma composition byadding an anti-arrhythmic agent to a platelet rich plasma composition.30. The method of claim 29, wherein the platelet rich plasma is preparedfrom whole blood of the patient.
 31. The method of claim 1, wherein theplatelet rich plasma composition comprises an anti-coagulant.
 32. Themethod of claim 1, wherein the platelet rich plasma compositioncomprises a clotting agent.
 33. The method of claim 1, wherein theconduction abnormality comprises a heightened risk of a cardiacarrhythmia.
 34. The method of claim 1, wherein the conductionabnormality is due at least in part to reperfusion therapy.
 35. A kitcomprising: one or more preparation devices for preparing platelet richplasma; one or more delivery devices configured to deliver a plateletrich plasma composition to conduction tissue of a heart; and one or moreanti-arrhythmic agents.
 36. The kit of claim 35, further comprisinginstructions for using one or more of the kit components.
 37. The kit ofclaim 35, further comprising one or more collection devices forcollecting blood from a patient who has suffered or is suffering fromthe cardiac arrhythmia.
 38. The kit of claim 35, wherein one of the oneor more preparation devices comprises a centrifuge.
 39. A methodcomprising: identifying a heightened risk of a cardiac arrhythmia in apatient; and delivering a platelet rich plasma composition to thepatient in an amount sufficient to treat the heightened risk of thecardiac arrhythmia.
 40. The method of claim 39, wherein identifying theheightened risk is based on a past history of a cardiac arrhythmia inthe patient.
 41. The method of claim 39, wherein identifying theheightened risk is based on acute ischemic tissue damage.
 42. The methodof claim 41, wherein the acute ischemic tissue damage has occurredwithin the last 24 hours.
 42. The method of claim 39, whereinidentifying the heightened risk is associated with reperfusion therapyto treat a myocardial infarction.
 43. The method of claim 42, whereindelivering the platelet rich plasma composition occurs within about 24hours of reperfusion therapy.
 44. The method of claim 43, whereindelivering the platelet rich plasma composition less than about 24 hoursbefore reperfusion therapy.
 45. The method of claim 43, whereindelivering the platelet rich plasma composition less than about 24 hoursafter reperfusion therapy.
 46. A method of reducing conductionresistance to an electrical stimulation device designed to maintaincardiac rhythm comprising delivering a composition comprising plateletrich plasma to an area of cardiac tissue, wherein said electricalstimulation device is operably coupled to cardiac tissue.
 47. The methodof claim 46 wherein the electrical stimulation device is a pacemaker.48. The method of claim 46 wherein the electrical stimulation device isan implanted cardiac defibrillation device.
 49. The method of claim 46,whereby resistance between the location wherein said electricalstimulation device is operably coupled to cardiac tissue and cardiacconductive tissue is reduced.
 48. The method of claim 49 wherein theelectrical stimulation device is a pacemaker.
 49. The method of claim 49wherein the electrical stimulation device is an implanted cardiacdefibrillation device.